The present invention relates generally to methods and devices used for delivery of remote ischemic preconditioning therapy. More particularly, the invention describes an approach to individualize the extent of the ischemic preconditioning stimulus depending on specific patient characteristics.
Ischemia-reperfusion (IR) injury is a composite result of damage accumulated during reduced perfusion of an organ or tissue, and the additional insult sustained during reperfusion. Such injury occurs in a wide variety of clinically important syndromes, such as ischemic heart disease and stroke, trauma, severe blood loss, etc. which are responsible for a high degree of morbidity and mortality worldwide.
During ischemia, anaerobic metabolism predominates and ATP production decreases. There is insufficient available energy to maintain cell membrane pump activity, anti-oxidant defenses, pH and calcium homeostasis, and mitochondrial integrity. These and other consequences of ischemia inevitably lead to cell death, unless blood flow is restored. Though reperfusion with oxygenated blood is essential for any tissue salvage, the sudden influx of oxygen leads to the formation of reactive oxygen species. A key event in cell death is mitochondrial permeability transition, a phenomenon that occurs when the mitochondrial permeability transition pore becomes permeable to molecules of about 1500 kDa or smaller. This leads to a rapid influx of small molecules, mitochondrial swelling and subsequent cell death.
Strategies to limit the duration of ischemia have achieved substantial health gains in myocardial infarction, and to a lesser degree, stroke. However, door-to-needle times have likely reached the minimum that is possible in many health-care delivery systems, so further reduction in morbidity and mortality from IR injury will require strategies to increase tissue tolerance to ischemia or reduce damage that occurs on reperfusion.
One such approach is ischemic preconditioning, and its variant—remote ischemic preconditioning. This treatment has been shown to be the most powerful intervention to stimulate innate resistance of tissues to ischemia-reperfusion injury. The term “ischemic preconditioning” is used in this description in a broad sense and includes a range of interventions known in the literature as “ischemic conditioning”, “ischemic peri-conditioning”, “ischemic per-conditioning”, and “ischemic post-conditioning”—in other words, it describes a series of intermittent ischemic episodes applied to a subject at some point before, during, or after the ischemic event and/or restoration of perfusion.
In general terms, the concept of remote ischemic preconditioning (RIPC) describes a series of intermittent occlusions of blood flow to a limb of a subject. Typically, a 5 min interval of occlusion is accomplished by inflating a cuff on a subject's upper arm to a sufficiently high cuff pressure. Deflation of the cuff causes release of occlusion and restoration of blood flow, which is maintained for another 5 min or so. This treatment cycle is repeated two or three times for a total duration of therapy of about 30-40 min.
RIPC activates three main cell-signaling pathways, the cyclic guanosine monophosphate/cGMP-dependent protein kinase (cGMP/PKG) pathway, the reperfusion injury salvage kinase (RISK) pathway, and the survivor activating factor enhancement (SAFE) pathway. Some of these pathways overlap, in particular where they converge on the mitochondria. Here, the potassium dependent ATP (KATP) channel is activated with evidence that this leads to closure of the mitochondrial permeability transition pore. RIPC also initiates a complex genomic and proteomic response that underpins the late phase of protection, including a plethora of anti-apoptotic and anti-inflammatory gene transcriptions.
Triggers in the initial cascade recruit early mediators such as protein kinase C (PKC), tyrosine kinase, phosphatidylinositol 3-kinases (PI3K), protein kinase B (PKB or Akt), mitogen-activated protein kinases (MAP1/2 or MEK1/2), extracellular signal-regulated kinases (Erk1/2), and janus kinase (JAK), which activate transcription factors such as signal transducer and activator of transcription proteins (STAT1/3), nuclear factor kappa-light-chain-enhancer of activated B cells (NFκB), activator protein 1 (AP-1), nuclear factor-like 2 (Nrf2) and hypoxia inducible factor 1α (HIF-1α). Systemic spread of protection involves both humoral and neuronal pathways.
A number of automatic devices and methods for delivery of remote ischemic preconditioning therapy have been described in the prior art. Caldarone (U.S. Pat. No. 7,717,855, US Patent Application Pub. Nos. 2011/0251635, 2010/0305607, 2010/0160799), Redington (PCT publication WO 2011/121402), Raheman (US Patent Application No. 2011/0238107), Naghavi (US Patent Application Pub. Nos. 2009/0287069, 2010/0105993, 2011/0319732), and my US Patent Application Pub. No. 2010/0324429 all describe various devices designed for this purpose. These documents are incorporated herein in their respective entireties by reference.
Activation of complex defensive response triggered by an ischemic preconditioning stimulus may be impaired in some categories of patients such as elderly or diabetics. Prior art devices have a predetermined and usually fixed preconditioning treatment protocol, which may not account for particular needs of such special patient groups. New devices and methods are therefore needed to provide as many patients as possible with the benefits of robust protection against reperfusion injury which are afforded as a result of applying remote ischemic preconditioning therapy.